Our laboratory is focused on using a genetic approach to isolate and understand genes contributing to the pathogenesis of the inherited forms of breast cancer, Long QT Syndrome and neural tube defects. Last year we discovered that a BRCA1 (185delAG) was carried by 1% of Ashkenazi Jews. This finding has major implications for genetic screening and public health. A follow up study (collaboration w/NCI) designed to determine the risk associated with being a 185delAG carrier has been initiated. Samples from over 5,000 volunteers have been collected. These samples have been tested for two BRCA1 mutations and one BRCA2 mutation. The results of this study will allow quantification of the cancer risk associated with each of these alleles. Studies of BRCA1 gene function are ongoing. The protein has been tested for DNA binding activity and association with other proteins. We have expressed the amino and carboxyl portions of the protein in bacteria. In collaboration with R. Klausner and J. Humphreys, BRCA1 has been expressed in yeast and a growth arrest phenotype observed. Studies of the long QT syndrome have culminated in the defining of specific mutations in long QT families and the completion of a contig of chromosome 11p15.5. We have cloned the human gene for methionine synthase (with James Mills, NICHD and Ruma Banerjee, U.NB, Lincoln). It is likely that this gene plays a role in the pathogenesis of neural tube defects (NTDs) and vascular disease. Patients with NTDs are now being analyzed for mutations in this gene. We have also determined that cbl-G patients have mutations in this gene.